Mammalian SCF (Skp1/Cul1/F-box protein) ubiquitin ligases are critical for the activation and attenuation of many cellular processes. They control complex molecular machines by directing the proteolysis of important regulatory elements in a precise, rapid, and localized manner. During the initial years of GM57587, we focused on the regulation of cyclin-dependent kinases (CDKs), which play pivotal roles in cell cycle control, and defined the key steps leading to the degradation of the CDK inhibitors p21 and p27 via the F-box protein Skp2. Moreover, we found that APC/CCdh1, an SCF-like ligase, controls Skp2 stability. We also demonstrated that TrCP, another F-box protein, allows precise regulation of the critical mitosis regulator Cdk1 by targeting Cdc25A, Claspin, Rest, and Emi1 for degradation. Finally, we found that three substrates that are targeted by SCF ubiquitn ligases in S and G2 are degraded via APC/C during different phases of the cell cycle (p21 in M, and Cdc25A and Claspin in G1). To broaden our understanding beyond CDK-centric roles of SCF complexes, we used unbiased screens and found that SCF, in addition to controlling the cell cycle, monitors and regulates multiple, seemingly disparate, cellular pathways, linking cell cycle control to protein synthesis, ribosomal biogenesis, cell survival, DNA-damage checkpoints, and the circadian clock. For example, we found that: the translation inhibitor Pdcd4 and the pro-apoptotic protein BimEL are degraded in a TrCP-dependent manner in response to growth and survival factors; Fbxl10 and Fbxl11 contribute to epigenetic regulation; Cyclin F/Fbxo1 prevents centrosome overduplication by targeting CP110 for degradation; and Fbxl3 is required to reset the circadian clock by promoting the proteolysis of the transcriptional repressors Cry1 and Cry2. We now propose a project exploring the integration of SCF-controlled cell cycle networks with DNA replication and DNA damage response. Via proteomic screens, we have identified novel putative SCF and APC/C substrates involved in these processes. We will characterize the mechanism and regulation of the degradation of these potential substrates in the context of DNA replication control (Aim 1), recovery from genotoxic stress (Aims 1 and 2), and mitosis (Aim 3).